Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

Background and Purpose: We assessed the contribution of antibody internalization in the efficacy and toxicity of intraperitoneal alpha-radioimmunotherapy (RIT) of small volume carcinomatosis using Pb-212-labeled monoclonal antibodies (mAbs) that target HER2 (internalizing) or CEA (non-internalizing) receptors. Materials and Methods: Athymic nude mice bearing 2-3 mm intraperitoneal tumor xenografts were intraperitoneally injected with similar activities (370, 740 and 1480 kBq; 37 MBq/mg) of Pb-212-labeled 35A7 (anti-CEA), trastuzumab (anti-HER2) or PX (non-specific) mAbs, or with equivalent amounts of unlabeled mAbs, or with NaCl. Tumor volume was monitored by bioluminescence and survival was reported. Hematologic toxicity and body weight were assessed. Biodistribution of Pb-212-labeled mAbs and absorbed dose-effect relationships using MIRD formalism were established. Results: Transient hematological toxicity, as revealed by white blood cells and platelets numbering, was reported in mice treated with the highest activities of Pb-212-labeled mAbs. The median survival (MS) was significantly higher in mice injected with 1.48 MBq of Pb-212-35A7 (non-internalizing mAbs) (MS = 94 days) than in animals treated with the same activity of Pb-212-PX mAbs or with NaCl (MS = 18 days). MS was even not reached after 130 days when follow-up was discontinued in mice treated with 1.48 MBq of Pb-212-trastuzumab. The later efficacy was unexpected since final absorbed dose resulting from injection of 1.48 MBq, was higher for Pb-212-35A7 (35.5 Gy) than for Pb-212-trastuzumab (27.6 Gy). These results also highlight the lack of absorbed dose-effect relationship when mean absorbed dose was calculated using MIRD formalism and the requirement to perform small-scale dosimetry. Conclusions: These data indicate that it might be an advantage of using internalizing anti-HER2 compared with non-internalizing anti-CEA Pb-212-labeled mAbs in the therapy of small volume xenograft tumors. They support clinical investigations of Pb-212-mAbs RIT as an adjuvant treatment after cytoreductive surgery in patients with peritoneal carcinomatosis.